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Integrated Chronic In Vivo and In Vitro Screens Uncover NFIL3 as a Driver of T-cell Dysfunction.
Nayan Jain1, Yuzhe Shi1, Celina May2,3
1Columbia Initiative in Cell Engineering and Therapy (CICET), Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, Columbia University, New York, New York.
Cancer Discovery
|February 26, 2026
Summary
NFIL3 drives dysfunction in CAR T cells, limiting their effectiveness against solid tumors. Disrupting NFIL3 enhances CAR T cell persistence and anti-tumor activity, offering a new therapeutic target for cancer immunotherapy.
Area of Science:
- Immunology
- Molecular Biology
- Oncology
Background:
- Chimeric antigen receptor (CAR) T cell therapy shows promise in hematological cancers but faces challenges in solid tumors due to limited T cell persistence.
- Understanding the molecular mechanisms behind CAR T cell dysfunction is crucial for improving their efficacy.
Purpose of the Study:
- To identify key regulators of CAR T cell dysfunction during chronic stimulation.
- To evaluate the therapeutic potential of targeting identified regulators to enhance CAR T cell function in solid tumors.
Main Methods:
- Conducted integrated chronic in vivo and in vitro screens of 400 transcription factors.
- Utilized genetic disruption of identified factors in CAR T cells.
- Assessed CAR T cell expansion, cytokine production, differentiation, and anti-tumor efficacy in mouse models.
Main Results:
- Identified NFIL3 as a critical driver of CAR T cell dysfunction.
- Genetic disruption of NFIL3 sustained CAR T cell expansion and cytokine production while restraining terminal differentiation.
- Loss of NFIL3 enhanced CAR T cell efficacy, improving tumor control and survival in preclinical models.
- NFIL3 disruption induced a transcriptional state associated with favorable clinical outcomes.
Conclusions:
- NFIL3 is a key determinant of CAR T cell functional decline in the tumor microenvironment.
- Targeting NFIL3 represents a promising strategy to enhance the efficacy of CAR T cell therapy for solid tumors.
- Integrated in vivo and in vitro genetic screening is a powerful approach for discovering therapeutic targets in cancer immunotherapy.
